Kisspeptin (encoded by Kiss1) is a key regulator of puberty and adult fertility, signaling directly to GnRH neurons through the kisspeptin receptor (Kiss1r). Additionally, Kiss1r is also expressed in other brain regions and in the periphery, suggesting that kisspeptin signaling may have additional roles outside of reproduction. Indeed, recent work indicates that kisspeptin neurons may regulate other neuronal populations implicated in feeding and energy balance. My novel and exciting preliminary data supports a role for kisspeptin signaling in metabolism, obesity, and glucose homeostasis. I found that adult Kiss1r knockout (KO) mice display a sexually dimorphic metabolic phenotype, with stark abnormalities in body weight, body composition, metabolic rate, and glucose homeostasis, which appears to be independent of activational actions of sex steroids. My novel findings support a role for kisspeptin signaling pathways in regulation of both the reproductive axis (via GnRH) and metabolic/energetic status (via unknown pathways). This NRSA project will provide new information on kisspeptin-Kiss1r signaling functions and has the potential to provide new insight into the interplay between reproduction and energy balance, and may translate to human metabolic diseases and infertility. This proposal's goal is to elucidate the causes of the pleiotropic and sexually dimorphic metabolic phenotype of the Kiss1r KO mice. Aim 1 determines if defects in metabolic rate precede the early adulthood obesity seen in Kiss1r KO females. This Aim examines several parameters using metabolic cages and hormone assays to determine the developmental onset of metabolic phenotypes in Kiss1r KO females. Aim 2 explores the role of potentially impaired leptin signaling and changes in hypothalamic metabolic genes in governing the obese phenotype of Kiss1r KO females. This Aim has two parts, the first of which assesses functional leptin responsiveness in Kiss1r KO mice at the cellular, and physiological, and behavioral levels. The second part of Aim 2 tests if expression levels of hypothalamic genes involved in food intake and metabolism are altered in Kiss1r KO females. Aim 3 determines if the dramatic sexual dimorphism in the Kiss1r KO phenotype is caused by developmental organization induced by neonatal sex steroids, and if so, via which sex steroid receptor pathways this occurs. Overall, this proposal will provide novel insight into the molecular and cellular mechanisms underlying the pleiotropic metabolic phenotype of mice with disrupted kisspeptin-Kiss1r signaling. This project will provide better understanding of the role of kisspeptin signaling at the interface between reproduction and metabolism, and may help to better understand the relationship between obesity and infertility.